Prodromal MS: Biomarkers

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Prodrome is the stage of a disease in which there are no noticeable symptoms, but nevertheless the disease is present. In MS this means that is a phase of MS in which there are no lesions, but there are alterations in the CNS.

This paper is about biomarkers for the MS prodromal phase.




Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis.

https://www.ncbi.nlm.nih.gov/pubmed/31566584
https://www.jci.org/articles/view/128475/ga

Multiple sclerosis (MS) is a disabling disease of the CNS. Inflammatory features of MS include lymphocyte accumulations in the CNS and cerebrospinal fluid (CSF).

The preclinical events leading to established MS are still enigmatic. Here we compared gene expression patterns of CSF cells from MS-discordant monozygotic twin pairs. Six "healthy" co-twins, who carry a maximal familial risk for developing MS, showed subclinical neuroinflammation (SCNI) with small MRI lesions. Four of these subjects had oligoclonal bands (OCBs). By single-cell RNA sequencing of 2752 CSF cells, we identified clonally expanded CD8+ T cells, plasmablasts, and, to a lesser extent, CD4+ T cells not only from MS patients but also from subjects with SCNI.

In contrast to nonexpanded T cells, clonally expanded T cells showed characteristics of activated tissue-resident memory T (TRM) cells. The TRM-like phenotype was detectable already in cells from SCNI subjects but more pronounced in cells from patients with definite MS. Expanded plasmablast clones were detected only in MS and SCNI subjects with OCBs.

Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded TRM-like CD8+ cells.

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More about the same:

DNA methylation signatures of a large cohort monozygotic twins clinically discordant for multiple sclerosis

https://www.biorxiv.org/content/early/2018/08/01/381822

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins that strongly argues for involvement of epigenetic factors. We observe in 45 MS discordant monozygotic twins highly similar peripheral blood mononuclear cell-based methylomes. However, a few MS-associated differentially methylated positions (DMP) were identified and validated, including a region in the TMEM232 promoter and ZBTB16 enhancer. In CD4+ T cells we observed an MS-associated differentially methylated region in FIRRE.

In addition, many regions showed large methylation differences in individual pairs, but were not clearly associated with MS. Furthermore, epigenetic biomarkers for current interferon-beta treatment were identified, and extensive validation revealed the ZBTB16 DMP as a signature of prior glucocorticoid treatment. Altogether, our study represents an important reference for epigenomic MS studies. It identifies new candidate epigenetic markers, highlights treatment effects and genetic background as major confounders, and argues against some previously reported MS-associated epigenetic candidates.

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Normalized cerebellar white matter and gray matter volume were significantly decreased in RIS compared to healthy controls.

Cerebellar volume loss in radiologically isolated syndrome

https://journals.sagepub.com/doi/abs/10 ... 8519887346

Abstract

Radiologically isolated syndrome (RIS), in which asymptomatic demyelinating-appearing lesions are detected incidentally on MRI, can be a pre-clinical form of multiple sclerosis (MS). In this study, we measured cerebellar volumes on 3D T1-weighted 3T MR images in 21 individuals with RIS and 38 age- and sex-matched healthy controls (HC). Normalized cerebellar white matter volume and the anterior cerebellar gray matter volume were significantly decreased in RIS compared to HC (p = 0.003 and p = 0.005, respectively). Our findings support reports of regional brain atrophy in RIS prior to the development of a seminal attack related to inflammatory demyelination.